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The four-symptom screen for active tuberculosis (TB) that is
recommended for all people living with HIV in lower-income settings is less
likely to detect active TB in people taking antiretroviral therapy (ART) and
may be improved by the additional use of a chest x-ray, according to a systematic review and
meta-analysis by the World Health Organization (WHO).

The findings are published in the journal The Lancet HIV.

TB remains the biggest cause of death in people
living with HIV, including those already taking ART. WHO estimated that nearly 400,000 people with HIV died of
TB in 2016. Preventing the development of active TB by giving
isoniazid preventive treatment is a priority for reducing the incidence of TB
in people living with HIV. TB prevention using isoniazid requires screening to
rule out active TB, as the use of isoniazid preventive therapy in a person with
active TB would lead to the development of isoniazid resistance.

An antibiotic that works by stopping the growth of bacteria. It is used with other medications to treat active tuberculosis (TB) infections, and on its own to prevent active TB in people who may be infected with the bacteria without showing any symptoms (latent TB).

When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.

To improve the uptake of isoniazid preventive treatment, WHO developed a four-symptom screening test that allows
physicians to rule out the presence of active TB. In the absence of current
cough, weight loss, night sweats or fever, TB preventive treatment can be
started. If any of the symptoms are present, further investigation is necessary.

A meta-analysis showed that this four-symptom screen had a
sensitivity of 79% and a specificity of 50% (in other words, the screen would correctly
identify active TB in 79% of people who had it and correctly rule out active TB
in 50% of people who do not have TB).

However, the four-symptom screen appears less sensitive in
people on ART, missing more cases of active TB than in
people not on ART. To determine the sensitivity and specificity of the
four-symptom screen in people on ART and to establish whether the use of a chest
X-ray would improve the sensitivity of screening in people on ART, WHO carried out a systematic review of studies and a
meta-analysis of study data.

The systematic review looked for studies published in journals or presented at conferences after
WHO recommended the four-symptom screen in 2011,
in which the sensitivity and specificity of the four-symptom screen was
verified with sputum or other samples, tested using culture or Xpert MTB/RIF.

The review identified 21 prospective cohort studies
involving 15,247 people with HIV. Ten studies included people taking ART but three
studies were excluded from the meta-analysis because they did not disaggregate
data according to ART status.

The meta-analysis covered 18 studies involving 4640 people
taking ART and 8664 people who were previously untreated at baseline. A median
of 68% of people with HIV had at least one of the four symptoms but the median
proportion of people on ART who had at least one symptom was lower, at 29.7%.

The meta-analysis found a pooled sensitivity of the
four-symptom screen in people on ART of 51% (95% CI 28.4-73.2) – that is to
say, the screen would identify only half of the people on ART who had active
TB. The specificity was 70.7% (95% CI 47.8-86.4%). In treatment-naïve people,
sensitivity was much higher in the pooled analysis (89.4%, 95% CI 83-93.4%),
but specificity was lower (28.1%, 95% CI 18.6-40.1%) than in ART-treated
people. However, when studies reporting no active TB in people not on ART were
excluded, sensitivity improved in people on ART (62.1%, 95% CI 38.4-81.1%) but
was almost unchanged in treatment-naïve people (88.5%, 95% CI 55-98).

Sensitivity of the four-symptom screen in people on ART was
higher in studies that did not include pregnant women (62.1%, 95% CI
38.4-81.1%) but specificity was lower (62.9%, 33.2-85.3%).

Five studies included data on chest x-ray findings. However, only
two studies provided data on 646 people that allowed the pooled sensitivity
and specificity of the four-symptom screen plus chest x-ray to be calculated in
people on ART.

These two studies suggested that adding the chest x-ray improved the sensitivity (84.6%, 95% CI 69.7-92.9%) but also substantially lowered the specificity (29.8%, 95% CI
26.3-33.6%).

The review authors say that the four-symptom screen may be
less sensitive in people on ART because people with low CD4 counts – more
likely to be initiating ART – are also more likely to present with symptoms of
fever or weight loss due to HIV disease or other opportunistic infections.

Although chest x-ray significantly improved the sensitivity
of screening in people on ART, the authors of an accompanying comment article,
Colleen Hanrahan and David Dowdy of the Johns Hopkins Bloomberg School of
Public Health, question whether the modest improvement in the probability of
detecting active TB in the absence of symptoms is worth the logistical and
financial challenges that national treatment programmes will face if they try to expand the use of chest x-ray.

“It is likely that a recommendation to require chest x-ray
before initiation of preventive therapy will do more harm than good,” they say,
pointing out that the reduction in the specificity of the four-symptom screen
if chest x-ray is added would reduce the number of people eligible for
isoniazid preventive treatment.

In the light of these findings,WHO has recommended that chest x-ray may be added to the four-symptom
screen in people who have already started ART.

Hamada Y et al. Sensitivity
and specificity of WHO’s recommended four-symptom screening rule for
tuberculosis in people living with HIV: a systematic review and meta-analysis.
The Lancet HIV, 5: e515-23, 2018.

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An international collaboration of infectious disease experts has identified a large group of people who appear to have naturally mounted an immune response to TB, a bacterial infection that is the leading cause of infectious disease death worldwide. Nearly 200 people from 2500 households with active TB were clearly exposed to TB for more than 10 years but the two most reliable tests (TST and IGRA) came back negative on repeated tests.

Study findings showed that a novel point-of-care tuberculosis test for patients with HIV offers superior diagnostic sensitivity to the currently available test while maintaining specificity, researchers reported.

The review author team found Xpert MTB/RIF to be sensitive and specific for diagnosing pulmonary TB and rifampicin resistance, consistent with findings reported previously. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for TB detection and similar sensitivity and specificity for rifampicin resistance detection (one study).

A study reported in Clinical Infectious Diseases this week confirms that patients newly diagnosed with HIV who were screened for TB with Xpert technology had higher survival rates in the year that followed than those screened with a point-of-care test using flourescent light-emitting microscopy.

Screening all hospitalized patients with HIV for tuberculosis using urine tests would improve life expectancy and be cost-effective in Malawi and South Africa, reports an international team of investigators led by Massachusetts General Hospital physicians.

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